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Christof Osman

The maintenance and inheritance of mitochondrial DNA

The viability and function of every eukaryotic cell crucially depends on its supply with energy. The majority of this energy is generated in mitochondria in the form of ATP by multisubunit-complexes of the respiratory chain in a process known as oxidative phosphorylation. While most of the subunits of the respiratory chain complexes are encoded in the nuclear genome and are imported into mitochondria post-translationally, a few essential subunits are encoded in the mitochondrial genome (mtDNA), which is thus absolutely essential for oxidative phosphorylation and mitochondrial and cellular function. mtDNA is present in tens to hundreds of copies in every cell, which are distributed throughout the tubular and reticulated mitochondrial network.

The reticulated mitochondrial network (red) and mtDNA (green) in a dividing cell of budding yeast. The image is derived from microscopy images. How does the cell evenly space copies of mtDNA?

Given the importance of mtDNA for cellular energy supply, it is not surprising that mutations within mtDNA have been identified as the cause for a multitude of human diseases and have been tightly linked to the ageing process and altered stem cell homeostasis. Accordingly, to ensure organismal health, good copies of mtDNA have to be faithfully inherited during cell division, their integrity needs to be maintained over generations and they need to be distributed throughout the mitochondrial network to provide all mitochondrial segments with mtDNA encoded proteins. Astonishingly, it remains poorly understood how cells accomplish these fundamental tasks. It is the aim of our lab to shed light on the mechanisms that underlie these fascinating processes.

A mitochondrial tubule (red) undergoes a fission event. mtDNA (green) segregates into both of the resulting ends. What are the molecular mechanisms that coordinate mtDNA segregation and mitochondrial fission?

We have developed a novel system in the yeast S. cerevisiae that for the first time allows minimally invasive tracking of mtDNA in living cells by high-speed live-cell fluorescence microscopy. We combine this live-cell imaging approach with super resolution microscopy, next-generation sequencing techniques and biochemical approaches to obtain unprecedented insights into the cellular principles and molecular mechanisms that govern distribution and inheritance of mtDNA and the maintenance of its integrity. While we exploit the unique experimental advantages of S. cerevisiae for many experiments in our lab, our ultimate goal is also to transfer our findings to higher eukaryotes to understand how dysregulated mtDNA distribution, inheritance or maintenance of its integrity affect human health.

The mutational landscape of mtDNA assessed by next-generation sequencing. The histogram on the inside represents the frequency of point mutations for WT (orange) or a yeast strain incapable of undergoing mitochondrial fusion and fission. The arcs represent genomic rearrangements of mtDNA. How is the integrity of mtDNA maintained?